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Stand Up For Science

10/02/11

Albert Sabin and the monkeys who gave summer back to the children.

Albert Sabin has been called “the doctor who gave summer back to the children.”*

Because of his decades of research to develop the oral polio vaccine, children today know nothing of the fear that polio brought to the United States every summer well into the 20th century. Swimming pools and movie theaters were closed and children were kept inside their homes by frightened parents. Worldwide, the disease killed millions of people and left legions of others permanently disabled.

We’ve just celebrated the 50th anniversary of the introduction of Dr. Sabin’s vaccine. Estimates suggest that in just its first two years of worldwide use, the vaccine prevented nearly 500,000 deaths and five million cases of polio. Today, the world is on the brink of realizing Dr. Sabin’s lifetime dream: the eradication of polio from the planet.

The development of the oral polio vaccine required years of extensive research with rabbits, monkeys and rodents.

Animal rights activists long ago seized on a single phrase by Dr. Albert Sabin, and have been using it ever since to try to support their outrageous claim that the developer of the oral polio vaccine(OPV) opposed the use of animals in research.

That phrase, “The work on prevention (of polio) was long delayed by an erroneous conception of the nature of the human disease based on misleading experimental models of disease in monkeys” spoken by Dr. Sabin during a congressional hearing in 1984, has been used in animal rights publications and comments for over two decades.

Dr. Sabin, a member of the Board of Directors of the pro-research Americans for Medical Progress until his death in 1993, spent years working to correct the record. Here is a letter he wrote to the editor of the Winston Salem Journal, published in 1992.

Winston-Salem Journal

March 20, 1992

The Correct Conclusion

In a recent letter to the Journal (“Misrepresenting Research,” Feb. 20), Dr. Stephen R. Kaufman, the chairman of the Medical Research Modernization Committee, correctly quoted my 1984 testimony before Congress but he drew wrong conclusions from it. Dr. Kaufman was also wrong when the said “the polio vaccine was based on a tissue culture preparation … not animal experimentation.”

On the contrary, my own experience of more than 60 years in biomedical research amply demonstrated that without the use of animals and of human beings, it would have been impossible to acquire the important knowledge needed to prevent much suffering and premature death not only among humans but also among animals.

In my 1956 paper in the Journal of the American Medical Association (Vol. 162, p. 1589), I stated that during the preceding four years “approximately 9,000 monkeys, 150 chimpanzees and 133 human volunteers were used thus far in studies of various characteristics of different poliovirus strains.” These studies were necessary to solve many problems before an oral polio-virus vaccine could become a reality.

Albert B. Sabin, M.D.

Washington”."

It is true that in the early years of polio research some lines of inquiry eventually proved unsuccessful. An overreliance on a strain of the virus known as the MV strain that had become adapted to survive only in nervous tissue, and the fact that the Rhesus macaque, while a good model for many aspects of polio, cannot be infected through ingestion via the mouth, led to the incorrect assumption that polio could only infect nerve cells (despite evidence to the contrary from both clinical studies and laboratory studies with other polio strains and monkey species). These mistakes were unfortunate, though understandable given the fact that virology as a science was in its infancy.

However, these failed attempts do not cancel out the fact that animal research, and research using monkeys in particular, was absolutely crucial to the development of vaccines for polio. Without it the polio vaccine would certainly not have been developed by the end of the 1950’s, and we might even still be waiting for it.

These vital contributions made by animal research to the development of polio vaccines were not limited to the work of Albert Sabin, and include:

(i) The discovery by Karl Landsteiner and Erwin Popper in 1908 that polio was caused by a virus, a discovery made by inoculating macaque monkeys with an extract of nervous tissue from polio victims that was shown to be free of other infectious agents.

(ii) The subsequent discovery by Simon Flexner that blood serum from infected macaque monkeys could protect against polio infection.

(iii) The discovery by Carl Kling and colleagues in 1911, following an earlier discovery that polio virus could be isolated from the lymph nodes of the small intestine of monkeys, that polio virus was present in the throat and intestinal tissues of people who dies from polio. Soon afterwards they isolated virus from the intestines of patients suffering from acute polio, and importantly from family members who did not display the symptoms of polio, establishing that healthy carriers played an important role in spreading the disease. In these studies the presence of polio was demonstrated by injecting filtered fluid from the patients into monkeys, the only method then available to confirm the presence of polio (Introduction to Epidemiology, fifth edition, by Ray M, Merill, Jones and Bartlett Learning).

(iv) The discovery in the early 1930’s by the Australian scientists Macfarlane Burnet and Jean Macnamara that antibodies against one strain of polio did not always protect macaque monkeys against infection with another strain.

(v) The discovery by John Enders, Thomas Weller and Frederick Robbins that the polio virus could be grown in a number of tissue types, not just nerve tissue as previously assumed, a discovery that required the use of mice and monkeys to prove that the cultured virus was indeed polio and still capable of causing paralysis.

It is hardly surprising that those close to Albert Sabin are disgusted with the way in which his views are misrepresented by animal rights activists. Writing for the Wall Street Journal two years after his death Albert Sabin’s widow, Heloisa Sabin, discussed the value of animals to his research.

ANIMAL RESEARCH SAVES HUMAN LIVES

The Wall Street Journal, October 18, 1995

by Heloisa Sabin

Mrs. Sabin is honorary director of Americans for Medical Progress.

That scene in "Forrest Gump," in which young Forrest runs from his schoolmate tormentors so fast that his leg braces fly apart and his strong legs carry him to safety may be the only image of the polio epidemic of the 1950s etched in the minds of those too young to remember the actual devastation the disease caused. Hollywood created a scene of triumph far removed from the reality of the disease.

Some who have benefited directly from polio research, including the work of my late husband, Albert Sabin, think winning the real war against polio was just as simple. They have embraced a movement that denounces the very process that enables them to look forward to continued good health and promising futures. This "animal rights" ideology -- espoused by groups such as People for the Ethical Treatment of Animals, the Humane Society of the U.S. and the Fund for Animals -- rejects the use of laboratory animals in medical research and denies the role such research played in the victory over polio.

The leaders of this movement seem to have forgotten that year after year in the early '50s, the very words "infantile paralysis" and "poliomyelitis" struck great fear among young parents that the disease would snatch their children as they slept. Each summer public beaches, playgrounds and movie theaters were places to be avoided. Polio epidemics condemned millions of children and young adults to lives in which debilitated lungs could no longer breathe on their own and young limbs were left forever wilted and frail. The disease drafted tiny armies of children on crutches and in wheelchairs who were unable to walk, run or jump. In the U.S., polio struck down nearly 58,000 children in 1952 alone.

Unlike the braces on Forrest Gump's legs, real ones would be replaced only as the children's misshapened legs grew. Other children and young adults were entombed in iron lungs. The only view of the world these patients had was through mirrors over their heads. These, however, are no longer part of our collective cultural memory.

Albert was on the front line of polio research. In 1961, thirty years after he began studying polio, his oral vaccine was introduced in the U.S. and distributed widely. In the nearly 40 years since, polio has been eradicated in the Western hemisphere, the World Health Organization reports, adding that with a full-scale effort, polio could be eliminated from the rest of the world by the year 2000.

Without animal research, polio would still be claiming thousands of lives each year. "There could have been no oral polio vaccine without the use of innumerable animals, a very large number of animals," Albert told a reporter shortly before his death in 1993. Animals are still needed to test every new batch of vaccine that is produced for today's children.

Animal activists claim that vaccines really didn't end the epidemics -- that, with improvements in social hygiene, polio was dying out anyway, before the vaccines were developed. This is untrue. In fact, advanced sanitation was responsible in part for the dramatic rise in the number of paralytic polio cases in the '50s. Improvements in sanitation practices reduced the rate of infection, so that the average age of those infected by the polio virus went up. Older children and young adults were more likely than infants to develop paralysis from their exposure to the polio virus.

Every child who has tasted the sweet sugar cube or received the drops containing the Sabin Vaccine over the past four decades knows polio only as a word, or an obscure reference in a popular film. Thank heavens it's not part of their reality.

These polio-free generations have grown up to be doctors, teachers, business leaders, government officials, and parents. They have their own concerns and struggles. Cancer, heart disease, strokes and AIDS are far more lethal realities to them now than polio. Yet, those who support an "animal rights" agenda that would cripple research and halt medical science in its tracks are slamming the door on the possibilities of new treatments and cures.

My husband was a kind man, but he was impatient with those who refused to acknowledge reality or to seek reasoned answers to the questions of life.

The pioneers of polio research included not only the scientists but also the laboratory animals that played a critical role in bringing about the end of polio and a host of other diseases for which we now have vaccines and cures. Animals will continue to be as vital as the scientists who study them in the battle to eliminate pain, suffering and disease from our lives.

That is the reality of medical progress.”

Animal rights activists are free to express their opposition to the use of animals in research, but they cannot do so by blatantly robbing society of scientific achievements. This one fact is clear -- if our critics had their way, today millions of children would be dead or disabled from polio and other infectious diseases.

* Of course Jonas Salk is equally, if not even more, deserving of this accolade.

Every day 1,000 Europeans die from stroke - that's one every 90 seconds - and about twice that number survive but are disabled...Our estimates are that hypothermia might improve the outcome for more than 40,000 Europeans every year."

This call does not come as a great surprise for me; when I was researching the role of animal research in the development of brain cooling to treat perinatal hypoxic-ischemic encephalopathy (HEI), a condition where a lack of oxygen and reduced blood supply during or shortly after birth causes brain damage, I found that all the papers I read cited animal studies of hypothermia to prevent damage in ischemic stroke. This is not surprising as in both conditions injury results from impaired blood supply.

IMAGE: CT image of an ischemic stroke. The dark area in top left quadrant of brain shows the damaged brain area. Welcome Images.

...we believe that hypothermia has been studied in sufficient detail and under a sufficiently broad variety of experimental conditions in animal models of ischemic stroke to support the translation of this treatment strategy to clinical trials”

In animal models of focal cerebral ischaemia, hypothermia improves outcome by about one-third under conditions that may be feasible in the clinic, with even modest cooling resulting in a substantial improvement in outcome. Cooling is effective in animals with co-morbidity and with delays to treatment of 3 h. Large randomized clinical trials testing the efficacy of moderate hypothermia in patients with acute ischaemic stroke are warranted”

This is important, as anyone familiar with stroke research will recognize Dr Macleod and Dr van der Worp as fierce critics of inadequate design and reporting of some preclinical animal studies, and of mistakes made when designing clinical trials due to the misinterpretation and misapplication of the results of animal studies. Quite often they found that the design of clinical trials was so different to the design of the preclinical study that it was impossible to tell whether the failure of a treatment in human patients actually contradicted the earlier success in an animal model, both outcomes were entirely plausible even if you assumed that there was absolutely no fundamental biological difference between the effects of stroke in the animal model and in human patients. For example, one problem is that the majority of neurprotective drugs evaluaded in the past few decades were shown to be effective in animal models of stroke only when administered very soon after induction of stroke - usually after less than half an hour - whereas in clinical trials there were usually long delays - four hours or more- before initiation of treatment. The fact that hypothermia has a neuroprotective effect in animal models up to three hours after stroke onset will make design of a clinical trial that matches the conditions under which treatment was successful easier, though as with all stroke treatment the earlier it is started the better!

It is notable that unlike animal rights campaigners who use deficiencies in some animal studies to call for a ban on it, Macleod and van der Worp understand its continuing importance to medical progress, and have worked with animal researchers to improve both the design and reporting of the preclinical animal studies that underpin the decisions to initiate clinical trials. Initiatives such as the ARRIVE guidelines are similar in many ways to recent improvements the design of clinical trials supported by the work of the Cochrane collaboration, and the widespread adoption of standards for the reporting of clinical trials.

So the animal evidence supporting the clinical initiation of trials of hypothermia for ischemic stroke had to satisfy a very strict panel of judges, we hope that funding is provided to initiate these important trials in the very near future.

16/12/10

From the bench and the bedside; how animal research is taming Multiple Sclerosis

Multiple sclerosis (MS) is one of the most common diseases of the central nervous system – the brain and spinal cord - affecting about one person in every thousand in the USA. It is an inflammatory condition, where the immune system attacks the myelin sheath that surrounds the axons of nerve cells. Myelin is a fatty material that insulates nerves, acting much like the covering of an electric wire and allowing the nerve to transmit its impulses rapidly. It is the speed and efficiency with which these impulses are conducted that permits smooth, rapid and co-ordinated movements to be performed with little conscious effort. Loss of myelin interrupts these impulses, and the nerve cells themselves are also damaged and eventually die.

The consequences for people with MS can be devastating, and MS is associated with a wide variety of symptoms, including muscle weakness, spasms, ataxia, problems with speech and vision, acute and chronic pain, and fatigue. MS is a very variable disorder, and the rate at which it progresses varies considerably from one patient to another, but a defining characteristic of it is the lesions that are visible by MRI where the myelin has come under attack. The relapses, attacks of worsening neurological function that are often found in MS, are closely associated appearance of new lesions in the CNS, although not all new lesions cause a relapse.

Until about 20 years ago there were no treatments available that could prevent relapses or slow the progression of MS – known as disease modifying treatments - but thanks to the efforts of scientists working around the word this situation has begun to change. A number of effective disease modifying treatments are now available, the most recent to receive FDA approval is Fingolimod (known as FTY720 during its development), a drug whose immunosuppressant properties in reducing transplant rejection and as a treatment for MS were evaluated in a range of animal models during its development.

One reason I say manageable rather than curable is that while these treatments are effective in reducing the number of relapses for many patients they do not work for all patients and all forms of MS (particularly for primary progressive MS), and can sometimes have serious side effects that prevent patients from continuing treatment. That is why scientists are continuing to study the biological mechanisms in MS, a disease whose origin is still not fully understood, though clinical and animal research indicates that both genetic and environmental factors play a role, their ultimate goal is to develop treatments that can stop relapses altogether.

Another reason for not referring to disease modifying treatments as “cures” is that they do not directly repair the damaged myelin sheath at the lesions. Spontaneous repair of the damaged myelin sheath in MS lesions does happen and plays an important role in limiting neurological damage, but until now the molecular basis of myelin regeneration by cells called oligodentrocytes, in the central nervous system (CNS) has been poorly understood. The Guardian reports on how scientists at the University of Cambridge have discovered how to promote remyelination in MS lesions by activating a population of stem cells in the CNS called oligodentrocyte precursor cells (1).

The team led by Professor Robin Franklin generated a comprehensive transcriptional profile of 22,000 genes during the separate stages of spontaneous remyelination that follow focal toxin-induced demyelination in the rat CNS, and found that the level of retinoid acid receptor RXR-gamma expression was increased during remyelination. Cells of the oligodendrocyte lineage expressed RXR-gamma in rat tissues that were undergoing remyelination, in both active lesions and in older remyelinated lesions. By examining post-mortem brain samples from MS patients, they were able to show that RXR-gamma expression was also elevated in oligodendrocyte precursor cells at the active lesion sites, supporting a general role for RXR-gamma in remyelination. Interesting as these findings were they did not demonstrate that RXR-gamma is actually required for remyelination, so they next performed studies to determine whether blocking the function of RXR-gamma would prevent remyelination.

Knockdown of RXR-gamma by RNA interference or RXR-specific antagonists severely inhibited the differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in culture. In mice that lacked RXR-gamma, adult oligodendrocyte precursor cells efficiently repopulated lesions after demyelination, but showed delayed differentiation into mature oligodendrocytes. The next question was whether increasing the activity of RXR-gamma would speed up remyelination. Administration of the RXR agonist 9-cis-retinoic acid to demyelinated mouse cerebellar slice cultures and then to aged rats in vivo after focal demyelination caused an increase in remyelinated axons. Focal toxin-induced demyelination was used to produce the lesions, rather than an immunity mediated model of demyelination such as experimental autoimmune encephalomyelitis, in order to determine that the increased remyelination was due to promotion of oligodendrocyte differentiation rather than to the anti-inflammatory effects of 9-cis retinoic acid.

The results indicate that RXR-gamma plays an important role in endogenous oligodendrocyte precursor cell differentiation and remyelination, and might be a pharmacological target for regenerative therapy in MS. The discovery that 9-cis-retinoic acid, a compound already in limited clinical use, can be used to stimulate myelin regeneration raises the possibility that within the next decade treatments that repair the neurological damage in MS will begin to enter clinical trials.

For people with MS these scientific and clinical advances are a great source of hope for a better future.

In advanced information accompanying today’s announcement the Nobel Assembly notes the importance of this research in laying the foundations for the development of human IVF by Bob Edwards and Patrick Steptoe, and also discusses how Bob Edwards' own extensive research on the reproductive biology of mice - and animal research he and his colleagues conducted in a variety of species while working on IVF - aided progress. In particular the Nobel Assembly highlights how his experience with mice in enabled Bob Edwards to solve a critical problem that was preventing successful IVF, by developing a way to harvest human egg cells at the optimal stage of their maturation prior to in vitro fertilization.

Without the decades of careful animal research undertaken by Bob Edwards, Gregory Pincus, Min Chueh Chang, and scores of their colleagues it is unlikely that IVF would ever have become a reality.

We heartily congratulate Professor Edwards on his Nobel Prize, an award that recognizes his outstanding contribution to a medical advance that has brought joy to hundreds of thousands of families around the world.

* Sadly Patrick Steptoe died in 1988 and therefore could not share the Nobel Prize with Robert Edwards.

22/09/10

Lasker awards highlight the contribution of animal research to medical progress

Each September the Albert and Mary Lasker Foundation recognizes the contribution made by scientists and doctors to medicine by awarding prizes to those who have made outstanding contributions to our understanding of disease, and to its treatment and prevention. The list of past recipients of these awards reads as a veritable who’s who of the greatest minds in medical research over the past 65 years, so it’s not surprising that the Lasker prizes are often called the “American Nobels”, indeed many Lasker prize winners have gone on to pay a visit to Stockholm not long afterwards.

As one might expect the Lasker prizes have often been awarded for discoveries and medical advances that relied on animal research, and this year is no exception.

The Albert Lasker Basic Medical Research Award went to Douglas Coleman and Jeffrey M. Friedman for their work on the hormone leptin, work that has led to a revolution in our understanding of the regulation of appetite and metabolism. The story of leptin is the story of how decades of careful research in mice led to an important discovery that is now helping to improve the lives of patients with rare genetic disorders, and more recently to help patients whose own leptin levels are too low as a result of HIV-related loss of fat tissue.

Napoleone Ferrara won the Lasker-DeBakey Clinical Medical Research Award for his discovery of the Vascular Endothelial Growth Factor (VEGF) and its role in regulating the growth of blood vessels. The description of Dr. Ferrara’s research on the Lasker website shows how Dr. Ferrara identified VEGF through research on cattle, and how his subsequent research using mice and rats ultimately resulted in the development of effective monoclonal antibody treatments for wet age related macular degeneration, a leading cause of blindness.

The third prize, the Lasker-Koshland Special Achievement Award in Medical Science, was awarded to Sir David Weatherall, a pioneer in the field of human genetics who has made invaluable contributions to our understanding of inherited blood disorders including α-or β-thalassemia and sickle cell anemia. His research laid the foundations for successful programs to reduce the incidence of these disorders, and of course to the development of treatments, some of which we discussed here just last week. Sir David may not have performed any animal research in his own career, but he recently chaired the committee which wrote an influential report on the role of primates in medical research. The report concluded that primate research has made an important contribution to medical progress, and is still needed in several important areas of medical research including neuroscience and vaccine development.

The message from this year’s Lasker prizes is clear; for medicine to continue to advance many different approaches to research must be applied, and among the many techniques that are necessary to progress animal research has an honored place.